Abstract Because axons of the central nervous system (CNS) fail to regenerate after injury, spinal cord trauma is a devastating cause of permanent neurologic disability in the veteran population. Work in recent years has begun to elucidate mechanisms responsible for the failure of regeneration, with identification of molecules expressed in CNS myelin whose interaction with axonal Nogo receptors results in the inhibition of axonal extension. The studies proposed are designed to test the hypothesis that: Functional ablation of the Nogo receptor family members NgR1 and NgR2 leads to improved motor behavior and axon regeneration following acute spinal cord injury. The research described in this grant application is aimed at testing the following hypothesis: Genetic ablation of the Nogo receptor family members NgR1 and NgR2 leads to improved motor behavior and axon regeneration following acute spinal cord injury in mice, and the corollary that local sustained production of a soluble chimeric NgR1/NgR2-Fc receptor will lead to enhanced axonal regeneration and improved behavioral outcomes following SCI and dorsal root crush in vivo. If NgR1 and NgR2 signal growth inhibition to regenerating axons, and do so in a partially redundant manner, the combined loss of NgR1 and NgR2 is anticipated to lead to an improved behavioral outcome compared to single knock-out mice or wild-type controls. Behavioral improvement will be compared to anatomical regeneration and sprouting of the corticospinal tract. In addition to the genetic approach in mice, we will test the therapeutic potential of a chimeric NgR1/NgR2 receptor expressed by gene transfer to neutralize myelin inhibition and promote axonal growth in a rat model of spinal cord and dorsal root injury in vivo. PUBLIC HEALTH RELEVANCE: Project Narrative Spinal cord injury is a serious problem in the veteran population, particularly for veterans of the OEF/OIF cohort. A major goal of spinal cord injury (SCI) research is to restore neuronal connectivity lost as a consequence of injury. The neuronal glycoproteins NgR1 and NgR2 have emerged as high affinity receptors for multiple myelin-associated inhibitors of growth. The proposed experiments will show whether the combined targeting of NgR1 and NgR2 improves behavioral outcomes and anatomical repair following SCIand plexus injuries in vivo. The mouse genetic studies will be complemented by a soluble Nogo-receptor gene therapy approach. The gene therapy experiments proposed are based on a newly developed reagent with potent CNSmyelin antagonistic properties, and if successful, may be developed rapidly for SCIstudies in non-human primates or clinical trials in spinal cord or plexus injury in humans.